Obesity is a worldwide problem, with an estimated number of obese adults of about 600 million. This epidemic of obesity is correlated with a great increase in the prevalence of obesity-related disorders, such as, for example, diabetes, hypertension, cardiac pathologies and liver diseases. Due to these highly disabling pathologies, obesity is currently considered in western countries as one of the most important public health problems. There is thus a real need of compositions and methods for treating or preventing obesity and/or obesity-related disorders.
Obesity and obesity-related diseases are associated with (i) metabolic dysfunctions (with an impact on glucose homeostasis and lipid metabolism for example); (ii) low grade inflammatory state associated to higher blood lipopolysaccharides (LPS) levels (also referred as metabolic endotoxemia); and (iii) impaired gut barrier function (i.e. increased gut permeability) leading to translocation of bacteria and/or microorganisms components into organs such as the liver or the adipose tissue. In order to treat obesity, impact on at least one, preferably 2 and more preferably 3 of these 3 factors is thus needed. These phenomena (i.e., intestinal inflammation, LPS and bacterial translocation) are also observed during inflammatory bowel diseases, such as for instance Crohn's diseases, colitis, ulcerative colitis, intestinal pain (e.g., colic) and other intestinal inflammatory diseases. Interestingly, both inflammatory bowel diseases and obesity-related diseases are associated with changes in the gut microbiota composition. Thus, reinforcing the gut barrier function is one of the major issues.
The human gut is colonized by a diverse, complex and dynamic community of microbes representing over 1000 different species, which continuously interact with the host (Zoetendal et al., 2008. Gut. 57(11):1605-1615; Rajilic-Stojanavic and de Vos, 2014. FEMS Microbiol. Rev. 38:996-1047). The homeostasis of the gut microbiota is dependent on host characteristics (age, gender, genetic background . . . ) and environmental conditions (stress, drugs, gastrointestinal surgery, infectious and toxic agents . . . ), but also on the day-to-day dietary changes.
It has been recently acknowledged that the intestinal microbiota is involved in a number of brain disorders, such as anxiety, autism (Hsiao et al., 2013. Cell. 155(7):1451-1463), Parkinson's disease (Scheperjans et al., 2015. Mov. Disord. 30(3):350-8), Alzheimer's disease (Harach et al., 2015. arXiv:1509.02273), and in multiple sclerosis (Berer et al., 2011. Nature. 479(7374):538-41).
Gut microbiota imbalance was also shown to be a risk factor for the development of cancers such as colorectal cancer (Zitvogel et al., 2015. Sci. Transl. Med. 7(271):271ps1; Louis et al., 2014. Nat. Rev. Microbiol. 12(10):661-72).
Growing evidences also support the role of gut microbiota in the development of obesity and related disorders (Delzenne & Cani, 2011. Annu. Rev. Nutr. 31:15-31) and intestinal inflammation (Wlodarska et al., 2015. Cell Host Microbe. 17(5):577-91), or intestinal pain (for example, babies' colic) (de Weerth et al., 2013. Pediatrics. 131:e550). In all these cases (obesity, intestinal inflammation, colic), dysbiosis of the microbiota can further disrupt the crosstalk between organs and the integrity of the intestinal barrier leading to symptoms.
Therefore, treatment with products that target the gut microbiota appeared as promising therapeutic tools for treating obesity and related disorders. These products may consist of living microbes, such as in the case of most probiotics, or contain dead microbes or fragments thereof. In addition, these products may comprise substrates that are used by the gut microbiota, such as in the case of prebiotics, or contain compounds that change the balance of the intestinal microbiota, such as specific antimicrobial compounds.
For example, WO 2008/076696 describes the gut microbiota as a therapeutic target for treating obesity and related disorders. WO 2008/076696 specifically describes methods for altering the abundance of Bacteroidetes and/or Firmicutes in the gut of a subject, by administering antibiotics and/or probiotics to the subject.
Moreover, EP 2 030 623 relates to the prevention and/or treatment of metabolic disorders, such as, for example, obesity related disorders, by regulating the amount of Enterobacteria in the gut. EP 2 030 623 discloses reducing the amount of Enterobacteria in the gut by administering probiotic bacteria, such as, for example, Bifidobacterium, Lactococcus, Streptococcus, Enterococcus or Lactobacillus. 
The patent application US 2012/083514 relates to infant cereals comprising non-replicating probiotic micro-organisms. US 2012/083514 describes three types of heat treatment: 140° C. for 15 seconds (ultra high temperature); 74° C., 90° C. and 120° C. for 15 seconds (high temperature short time); and 85° C. for 20 minutes (long time low temperature). However, it is shown in this patent application US 2012/083514 that the ratio IL12/IL10 strongly increases in bacteria submitted to heat treatment at 85° C. for 20 minutes. IL12 is a proinflammatory cytokine, while IL10 is an anti-inflammatory cytokine. US 2012/083514 thus demonstrates that a heat treatment at 85° C. for 20 minutes increases the inflammatory state of the subject and is therefore not recommended for treating inflammatory disorders. Meanwhile, US 2012/083514 demonstrates that bacteria have to be heated for a very short time (15 seconds) to present an anti-inflammatory profile.
Furthermore, the Applicant described that the gut microbiota is modified in prebiotic-treated obese mice (Everard et al., 2011 November Diabetes. 60(11):2775-86). Moreover, prebiotics (1) improve glucose and lipid metabolisms in obese and diabetic mice, (2) reduce plasma LPS and improve gut barrier function (e.g. reduction of inflammation) in obese mice, (3) induce an increased enteroendocrine L-cell number in obese and diabetic mice, and (4) improve leptin sensitivity and glucose homeostasis in diet-induced obese and diabetic mice.
The Applicant also described the use of Akkermansia muciniphila or fragments thereof for treating obesity and related disorders (WO 2014/076246). Moreover, the Applicant also disclosed a reduced abundance of Akkermansia muciniphila in the gut of patients suffering from ulcerative colitis (Rajilić-Stojanović M et al., 2013 March Inflamm. Bowel Dis. 19(3):481-8). In Crohn's disease mainly butyrate-producing bacteria were found to be depleted (Wlodarska et al., 2015. Cell Host Microbe. 17(5):577-91). However, it was shown that Akkermansia muciniphila, which produces the short chain fatty acids propionate and acetate, can also give rise to trophic chains that produce butyrate as end product from mucus. Butyrate is known to reduce pain sensation in the gut and, like acetate and propionate, is known to show immune signaling. Finally, it has been shown that addition of Akkermansia muciniphila increases the barrier function in a human cell line (Reunanen et al., 2015. Appl. Environ. Microbiol. 81(11):3655-62). Hence, it is very likely that Akkermansia muciniphila and its products may reduce intestinal pain and inflammation as well as reinforce the gut barrier in healthy human as well as in patients suffering from intestinal inflammatory diseases. This may not only apply to adults but also to infants, as reduced butyrate producers were associated with excessive crying in baby colic and atopic diseases in young infants (de Weerth et al., 2013. Gut Microbes. 4(5):416-21; Nylund et al., 2015. Allergy. 70(2):241-4).
However, here, the Applicant surprisingly showed that administration of pasteurized Akkermansia muciniphila is more efficient than non-pasteurized Akkermansia muciniphila to increase barrier function and treat metabolic dysfunctions associated with obesity and related disorders. The present invention thus relates to the use of pasteurized Akkermansia muciniphila or fragments thereof to increase barrier function and treating obesity and related disorders.